Cyclin D1 represents an important downstream effector of diverse proliferative and transforming signaling pathways, including those mediated by β-catenin (Shtutman et al., 1999), ERα (Lukas et al., 1996; Prall et al., 1998; Wilcken et al., 1997), Her-2/Neu (Lee et al., 2000), NFκB (Henry et al., 2000; Joyce et al., 1999), Rac (Westwick et al., 1997), Ras (Albanese et al., 1995), Src (Lee et al., 1999), STATs (Bromberg et al., 1999; Matsumura et al., 1999), and Wnt (D'Amico et al., 2000). In mammary cells, transcriptional activation of cyclin D1 in response to these mitogenic signals leads to G1/S progression and increased proliferation. Cyclin D1 overexpression has been implicated in oncogene-induced mammary tumorigenesis as it is noted in over 50% of primary breast carcinomas correlating with poor prognosis (Kenny et al., 1999; McIntosh et al., 1995). In addition to activating cyclin-dependent kinases (CDKs) and sequestering of CDK inhibitors in the G1/S transition, the function of cyclin D1 as a CDK-independent activator of estrogen receptor α (ERα) is especially noteworthy (Lamb et al., 2000; McMahon et al., 1999; Neuman et al., 1997; Zwijsen et al., 1997). Cyclin D1 overexpression confers resistance to antiestrogens in breast cancer cells (Hui et al., 2002; Musgrove et al., 2001), and represents a negative predictive factor for tamoxifen response (Stendahl et al., 2004). Together, these findings suggest that an anti-cyclin D1 therapy might be highly specific for treating human breast cancer (Yu et al., 2001).
Accordingly, a need exists for new cyclin D1 ablative agents useful in the treatment of cancers, particularly breast cancers.